Efficacy and Safety of Methotrexate versus Placebo in Adults with Atopic Dermatitis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medac Gesellschaft fuer klinische Spezialprapaerate mbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

Trial duration

29 Jan 2024 → ongoing

Decision date (initial)

2023-11-21

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Medac Gesellschaft fuer klinische Spezialprapaerate mbH

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To demonstrate the superiority of subcutaneous (SC) methotrexate (MTX) versus placebo with respect to an improvement from baseline of at least 75% of the Eczema Area and Severity Index (EASI 75 response) at the Trial Week 16 Visit in adult participants with moderate to severe atopic dermatitis (AD)

Secondary objectives 4

1. To compare the efficacy of MTX (SC) versus placebo at different defined timepoints in participants with moderate to severe AD
2. To compare the safety and tolerability profiles of MTX (SC) versus placebo in participants with moderate to severe AD
3. To compare the quality of life of participants treated with MTX (SC) versus placebo at different defined timepoints in participants with moderate to severe AD
4. To evaluate the maintenance of the efficacy of MTX versus placebo in participants during the extension phase

Conditions and MedDRA coding

moderate to severe atopic dermatitis

Regulatory references

Scientific advice from competent authorities

Swedish Medical Products Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Male or female adult (ie, aged 18 years or older)
2. Woman of childbearing potential must have a negative pregnancy test at the Screening Visit and must agree to use highly effective methods of contraception while taking the IMP and for 6 months after the last IMP administration. Men must agree to use a condom during intercourse while taking the IMP and for 3 months after the last IMP administration. They must also agree to not donate sperm for the time period starting at the Screening Visit, throughout the entire trial period, and for at least 3 months after the last IMP administration.
3. Diagnosis of AD at least 12 months prior to the Screening Visit, diagnosed as defined by the Hanifin and Rajka criteria for AD
4. Moderate to severe AD, defined as the following criteria at the Baseline Visit: EASI ≥ 16, IGA ≥ 3, DLQI ≥ 10
5. Eligible for systemic treatment, ie, documented history (within 12 months prior to Baseline Visit) of inadequate response to treatment with TCS or TCIs or documented systemic treatment for AD (such as CsA, azathioprine and/or mycophenolate mofetil). Inadequate response to TCS or TCI is defined as failure to obtain or maintain a remission or a low activity disease (IGA ≥ 2) despite a daily treatment with a class 2 or class 3 TCS or TCI for 28 days (or the maximal authorised duration according to the SmPC)
6. Treated with a stable dose of topical emollient, for at least 7 consecutive days prior to the Baseline Visit. Treatment with more than 1 emollient is acceptable.
7. Chest X-ray without clinically relevant abnormalities performed within the last 6 months prior to the Baseline Visit
8. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
9. Willing and able to comply with the protocol requirements for the duration of the trial
10. Covered by health care insurance in accordance with local requirements

Exclusion criteria 25

1. Pregnant or breast-feeding women, or planning to become pregnant, or to breastfeed during the trial
2. Previously treated with MTX
3. Presenting a known hypersensitivity to MTX or folic acid as well as to any of the excipients
4. Presenting ulcers of the oral cavity and known active gastrointestinal ulcer disease
5. Presenting with known blood dyscrasia (haemoglobin < 8.0 g/dL or white blood cell count < 4000/mm3 or platelet count < 100000/mm3)
6. Presenting liver impairment and/or AST or ALT > 2 times the upper limit of normal (ULN), or bilirubin > 5 mg/dL (85.5 µmol/L), or a positive result in the FibrotestTM at the Screening Visit
7. Presenting drug or alcohol abuse within the last 12 months
8. Presenting renal impairment (creatinine clearance less than 60 mL/min)
9. Presenting serious, acute or chronic infections such as tuberculosis, hepatitis B or C, HIV positive, or other immunodeficiency syndromes.
10. Presenting uncontrolled infection, hospitalisation due to uncontrolled infection or treatment with intravenous antibiotics for infection within 2 months prior to the Baseline Visit
11. Presenting a history of malignancy, including solid tumours and haematologic malignancies, except non-melanoma skin cancer (epithelial cell carcinoma or basal cell carcinoma) and cervical carcinoma in situ that have been treated with no evidence of recurrence during the past 5 years
12. Currently experiencing or having a history of other concomitant skin conditions that would interfere with evaluation of AD (eg. psoriasis, lupus erythematosus, eczema herpeticum)
13. Treated with an investigational drug within 8 weeks or within 5 half-lives (if known), whichever is longer, before the Baseline Visit
14. Treated with TCS, calcineurin inhibitors or phosphodiesterase-4 inhibitors such as crisaborole within 1 week prior to the Baseline Visit
15. Treated with oral corticosteroids, azathioprine, mycophenolate mofetil, CsA or any other systemic immunosuppressor / immunomodulator within 4 weeks before the Baseline Visit
16. Treated by specific allergen immunotherapy within 3 months before the Baseline Visit
17. Treated with a monoclonal antibody (including but not limited to dupilumab or tralokinumab) within the last 3 months or 5 times the half-life of the respective monoclonal antibody (whichever is the longer period) or with any JAK inhibitors (including but not limited to ruxolitinib, baricitinib, tofacitinib, upadicitinib, or abrocitinib) within the last 4 weeks prior to the Baseline Visit
18. Treated with any parenteral corticosteroid within 6 weeks prior to the Baseline Visit
19. Treated with ultraviolet therapy within 4 weeks prior to the Baseline Visit
20. Received a live (attenuated) vaccine within 4 weeks before the Baseline Visit or planning to be vaccinated with live vaccine during the trial
21. Having a planned surgery during the trial
22. Presenting a clinically significant medical disease that is uncontrolled despite treatment that, in the opinion of the Investigator, is likely to impact the ability to participate in the trial or to impact the trial efficacy or safety assessments
23. Presenting any additional condition that, in the opinion of the Investigator, may interfere with the assessment or may put the participant at risk
24. Protected by the law (adult under guardianship, or hospitalised in a public or private institution for a reason other than this trial, or incarcerated)
25. Persons performing mandatory military service, persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical trials, and persons, who due to their age, disability or state of health are reliant on care and for that reason accommodated in residential care institutions, that is accommodations providing an uninterrupted assistance for persons who necessitate such assistance, are in a situation of subordination or factual dependency and therefore may require specific protective measures

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. EASI 75 response at the Trial Week 16 Visit

Secondary endpoints 4

1. EASI, SCORAD, IGA, NRS and POEM scores or responses at different time points including Trial Week 4, Trial Week 8, Trial Week 12 and Trial Week 16
2. Adverse events (AE), treatment-related AEs, serious adverse events (SAEs) occurring from the Screening Visit until the Trial Week 16/24 Visit, and serious adverse reactions (SARs) occurring from start of the trial intervention until Trial Week 20/33 Visit - time points depending on participation in the extension phase or not. Change in vital signs and laboratory values.
3. Change in DLQI, SCORAD, WPAI:GH, HADS, EQ-5D-5L and ADCT scores or responses from baseline to different time points including Trial Week 4, Trial Week 8, Trial Week 12, and Trial Week 16
4. EASI, IGA, NRS, SCORAD, DLQI, WPAI:GH, HADS, EQ-5D-5L and ADCT responses at Trial Week 24 or change in scores or responses between Trial Week 16 and Trial Week 24

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medac Gesellschaft fuer klinische Spezialprapaerate mbH

Sponsor organisation

Medac Gesellschaft fuer klinische Spezialprapaerate mbH

Address

Theaterstrasse 6

City

Wedel

Postcode

22880

Country

Germany

Scientific contact point

Organisation

Medac Gesellschaft fuer klinische Spezialprapaerate mbH

Contact name

Clinical Trial Information

Public contact point

Organisation

Medac Gesellschaft fuer klinische Spezialprapaerate mbH

Contact name

Clinical Trial Information

Third parties 9

Locations

4 EU/EEA countries · 31 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 73 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

14 submissions — initial application plus substantial / non-substantial modifications